Hepatitis C virus (HCV) infection is the leading indication for liver transplant in the United States. Infection with HCV frequently leads to liver cirrhosis and is linked to the development of hepatocellular carcinoma. Current HCV therapies effectively control viral replication in only 30-50% of people infected. New treatment strategies are needed to combat the 3-4 million new HCV infections occuring world-wide each year. Recently, the pharmaceutical industry has taken great interest in developing potent HCV protease and polymerase inhibitors. While many of these compounds have shown great promise in clinical trials, the development of inhibitor resistance is a very real concern. HCV variants resistant to potential inhibitors have been selected in culture primarily using the HCV genotype 1 b sub-genomic replicon. It is not clear if the replicon system is limited in its ability to determine the impact of resistance mutations on viral escape and fitness since it cannot produce infectious virions. The recent identification of HCV variants capable of replicating in cell culture and in chimpanzees will allow for the comparison of these two systems to determine which one most accurately represents what will occur in vivo. The aim of this proposal to determine what differences, if any, exist in the ability of these two systems to recreate the viral dynamics involved in the development of inhibtor resistance. Understanding the viruses ability to select for and tolerate resistance mutations will be valuable in determining the types of inhibitors used for treatment as well as for developing effective combination therapies.